Determination of protective efficacy of multimeric Shigella vaccine as the next step toward human trials

SUMMARYShigellosisbacillary dysenteryis a severe bloody diarrhea that occurs worldwide and for which there is no licensed vaccineThis disease is particularly devastating in low income regions of the world where clean water and proper sanitation are lackingMortality and morbidity are highest in children under the age ofwith survivors exhibiting impaired growth due to malnutritionShigella sppare also common pathogens associated with diarrheal outbreaks in crowded settings such as among refugees and military personnelIndeedit was recently reported that the U Shad lostmillion service days in Iraq and Afghanistan due to Shigella sppThe Shigella sppinvasive phenotype requires a type III secretion systemT SSand the T SS apparatusT SAwhich resembles a molecular syringe and needleis the energized conduit that delivers effector proteins directly into target cells to hijack normal cellular functionsA needle tip proteinIpaDand the first translocator proteinIpaBlocalize to the distal end of the T SA needleIpaB and IpaD are required for pathogenesis and each is highly conserved among the shigellaebeingandidentical among all virulent Shigella strainsrespectivelyThe genus Shigella includes four species but andgtserotypes with new serotype variants continually emergingThuswe have developed a serotype independent vaccine by genetically fusing IpaB and IpaD to produce the novel fusion proteinDBFDBFadmixed with dmLTthe adjuvant double mutant labile toxin from Enterotoxigenic Ecoli and delivered intranasally or parenterallyprotected mice against lethal challenges by homologous Sflexneri and heterologous Ssonnei and SdysenteriaeFurthermoreDBF dmLT administered parenterally protectedof monkeys from severe diarrhea after the heterologous Ssonnei challengeUnfortunatelyhumans typically do not respond well to recombinant antigens of a monomeric natureThereforewe have developed hyaluronan polyvalent adjuvant fusion technologyHafa complex nanoparticle containing a carrieradjuvantand the fusion antigenWith this technologythe loaded nanoparticle is targeted for capture by dendritic cellswhich deliver the protein cargo to lymph nodesmimicking a bacterial infectionThe nanoparticles remain at the lymph node germinal centers for extended periods eliciting a stronger immune response than the monomer with prolonged memoryThusalthough DBF dmLT has been shown to protectof monkeys from severe diarrhea caused by Ssonneiwe hypothesize that the nanoparticle that is Haf DBF will elicit a robust immune response by taking advantage of the ability of the hyaluronan component of Haf to invoke recruitment of antigenpresenting cellsAPCsincreased lymphoid tissue exposure of adjuvant antigenand Haf mediated clustering of antigen to mimic a natural infection NARRATIVEShigellosis is a severe dysentery that occurs throughout the world and for which there is no licensed vaccineThis disease is particularly devastating in low income regions of the world where clean water and proper sanitation are lackingWe propose to develop a vaccine by taking advantage of hyaluronan and proteins from the pathogen